Project Summary In general, the cerebral metabolic rate of oxygen (CMRO2) closely parallels blood flow. However, regional un- coupling of this relationship is well known to occur in many instances. Soon after its discovery, the blood oxy- gen level dependent (BOLD) contrast had become the main pillar of functional magnetic resonance (fMRI). However, the BOLD effect -- a change in gradient-echo signal in response to neural stimulation -- is a compli- cated function of cerebral blood flow (CBF), deoxyhemoglobin (dHb) concentration and capillary blood volume. Typically, the BOLD effect is positive since accumulation of dHb due to a local increase in CMRO2 is far ex- ceeded by the effect of increased blood flow, thereby more than offsetting the signal loss that would be ex- pected from increased oxygen extraction alone. In recent years there has been growing interest in measuring the change in response to functional tasks or vasoactive stimulants by dissecting the BOLD signal into its components to yield DCMRO2, the task- induced change in CMRO2. Two approaches have emerged, referred to as quantitative BOLD (qBOLD) and calibrated BOLD (cBOLD). Both models exploit the paramagnetism of dHb by eliciting a disturbance of the magnetic field in the intra- and extravascular space. QBOLD yields baseline CMRO2 in physiologic units but may not be suited for quantifying dynamic changes. In contrast, cBOLD provides typically provides the frac- tional change DCMRO2/CMRO2. The crux of cBOLD is the voxelwise determination of the calibration constant M that relates the measured change in the BOLD signal to a function of the fractional CMRO2 and CBF chang- es based on a hypercapnia challenge. Once M is known regional CMRO2 changes in response to neural stimu- lation can be determined with relatively high temporal resolution. However, the approach is limited by relying on questionable assumptions and suffering from sensitivity to measurement errors. Here, we propose the de- velopment, validation, and application in a pilot study, of a new cBOLD pulse sequence and analysis approach. The method, referred to as OxBOLD, building on our prior work in whole-brain oximetry, consists of an inter- leaved pulse sequence that measures the change in CBF and oxygen saturation in response to a well- tolerated hyperoxia challenge. We show in preliminary work that the new method yields calibration constants of superior quality. The four specific aims comprise (1) implementation, (2) technical performance evaluation, (3) testing in response to well-established neural stimuli to derive their effect on CMRO2 in comparison to BOLD, and (4) application of the method in a translational pilot study. The latter involves a subset of patients with ob- structive sleep apnea, currently studied under R01 HL122754, to evaluate the hypothesis that in these patients the CMRO2 response to volitional apnea, used as a model for spontaneous apneas, is blunted in an anatomic region-specific manner, thereby providing insight into the neurometabolic consequences of the disease and the cognitive impairment known to affect these patients.